Method for chemically synthesizing berberine hydrochloride

Abstract

The invention discloses a method for chemically synthesizing berberine hydrochloride. The method comprises the following steps: firstly, synthesizing a methyl substance; synthesizing a condensation compound; then, berberine hydrochloride is synthesized; the synthesis method has the advantages of cheap and easily available raw materials, less generated three wastes, environmental protection, no use of a heavy metal catalyst, no drug safety risk caused by excessive heavy metals in the finished product, no high-temperature and high-pressure reaction, mild reaction conditions, simple required equipment, convenient operation and good controllability, and is suitable for large-scale industrial production; the purity of berberine hydrochloride produced through the method can reach 99.8% or above, the single impurity content is smaller than 0.1%, and the medicine safety and effectiveness are greatly guaranteed.

Description

Technical Field

[0001] The invention belongs to the technical field of pharmaceutical synthesis methods, and specifically relates to a method for chemically synthesizing berberine hydrochloride. Background Art

[0002] The chemical name of berberine hydrochloride is: 5,6-dihydro-9,10-dimethoxybenzo[g]-1,3-benzodioxolane[5,6-α]quinolizine hydrochloride dihydrate, molecular formula: C20H18ClNO4, English name: Berberine hydrochloride, it is a yellow crystalline powder, odorless; it dissolves in hot water, is slightly soluble in water or ethanol, and is almost insoluble in ether.

[0003] Berberine hydrochloride is an isoquinoline alkaloid, also known as berberine. Berberine is a quaternary ammonium alkaloid. Berberine can be treated with different bases to obtain three different forms of berberine, including quaternary ammonium, aldehyde and alcohol. Among them, the quaternary ammonium form is the most stable. Berberine has antibacterial effects on hemolytic streptococci, Staphylococcus aureus, gonococci, and Shigella dysenteriae, and enhances the phagocytic effect of leukocytes. It has been widely used in the treatment of gastroenteritis, bacterial dysentery, etc. It also has certain effects on tuberculosis, scarlet fever, acute tonsillitis and respiratory tract infections. In recent years, a large number of studies and clinical applications have shown that berberine also has anti-tumor, anti-viral, anti-HIV, diabetes, anti-obesity, anti-malaria, anti-rheumatic, anti-aging, anti-anxiety, and anti-rejection of living organ transplants.

[0004] The following problems often exist in the existing berberine hydrochloride preparation process:

[0005] 1) Long steps and low yield;

[0006] 2) High temperature and high pressure reaction, poor safety;

[0007] 3) Poor crystallinity and difficult filtration;

[0008] 4) The purity of the finished product is low, with the maximum single impurity reaching more than 0.9%, and multiple impurities do not meet the ICH Q3A standard of organic impurities ≤ 0.10%. Summary of the invention

[0009] The object of the present invention is to provide a method for chemically synthesizing berberine hydrochloride to solve the problems raised in the above background technology.

[0010] To achieve the above object, the present invention provides the following technical solution: a method for chemically synthesizing berberine hydrochloride, the specific steps comprising: S1: synthesis of methyl compound;

[0011] S11: Add o-vanillin and acetone to the reaction bottle, stir to dissolve, then pour in anhydrous potassium carbonate, and continue to stir evenly;

[0012] S12: Pour dimethyl sulfate into the mixture, heat the mixture to 25-55°C and stir for 6-10 hours. After the reaction is completed under TLC monitoring, concentrate the reaction solution to dryness;

[0013] S13: adding purified water and organic solvent for extraction, separating the water layer, retaining the organic layer, and concentrating to dryness to obtain a yellow-brown oily substance, namely 2,3-dimethoxybenzaldehyde;

[0014] S2: Synthesis of condensation products;

[0015] S21: directly add piperidine to the reaction bottle containing the oil obtained in S13, turn on the heating and vacuum pump, maintain the temperature in the autoclave at 90°C-110°C and the pressure at 0.085 MPa, and stir to react for 1 hour;

[0016] S22: When the reaction time is up, cool down, release the pressure with nitrogen, add solvent to dilute, stir to dissolve, cool down to below 10°C, add reducing agent to the reaction bottle in batches, and continue stirring for 1-3h after addition;

[0017] S23: After the reaction was completed by TLC monitoring, the temperature was kept at 0-10°C, hydrochloric acid was added dropwise to adjust the pH value to 2-3, a large amount of solid was precipitated, the temperature was lowered to -5°C, crystallization was carried out for 8-12 hours, centrifuged, and air-dried at 60°C for 5 hours to obtain an off-white condensation product;

[0018] S3: Synthesis of berberine hydrochloride;

[0019] S31: Add formic acid and copper sulfate to the reaction flask, stir and heat to 55-60°C and keep warm for 30 minutes;

[0020] S32: Continue to add the condensate obtained in S23 and glyoxal, raise the temperature to 90-110°C for reaction, and add concentrated hydrochloric acid 0.1-0.12 m / m to the reaction system every hour during the reaction, for a total of 5 times;

[0021] S33: After 5 hours of addition, cool to 15-25°C and stir for 30 minutes, centrifuge, wash the filter cake with purified water until the pH of the mother liquor reaches 3-5, and stop centrifugation;

[0022] S34: Add the wet filter cake back into the reaction flask, add purified water, stir for 30 minutes, then add ammonia water, heat to 25-45°C and stir for 2 hours, cool to 10-20°C and filter, wash the filter cake with purified water, add the wet filter cake into the reaction flask, add 5-10% isopropanol aqueous solution, heat to 85-95°C and keep warm for 1 hour, add activated carbon and stir for 30 minutes;

[0023] S35: Filter again into a reaction bottle pre-filled with 5-10% hydrochloric acid, stir for 30 minutes, cool to 15-25°C, stand for crystallization for 8-12 hours, centrifuge, wash the filter cake with purified water, and dry at 80°C for 8-10 hours to obtain the berberine hydrochloride product.

[0024] Preferably, in S11 and S12, the mass ratio of o-vanillin:potassium carbonate:dimethyl sulfate is 1:1.1-1.2:0.95-0.98.

[0025] Preferably, in S13, the organic solvent is any one of toluene, ethyl acetate and dichloromethane.

[0026] Preferably, in S21, the mass ratio of piperonyl ethylamine to o-vanillin is 1.05-1.08:1.

[0027] Preferably, in S22, the reducing agent is sodium borohydride; the mass ratio of sodium borohydride: o-vanillin is 0.12-0.17:1, and after the reaction is completed, dilution with methanol or ethanol is performed and hydrochloric acid is directly added dropwise to form a salt.

[0028] Preferably, in S31, the concentration of formic acid is any one of 85% formic acid, 88% formic acid, and 90% formic acid, and the content of glyoxal in S32 is 40%.

[0029] Preferably, in S3, the mass ratio of condensate: copper sulfate: glyoxal: formic acid is 1:0.90-0.95:0.70-0.75:5.

[0030] Preferably, in S32, the mass ratio of hydrochloric acid added each time during the reaction: condensate is 0.12-0.17:1, and the interval between each addition is 1 hour.

[0031] Preferably, in S34, the mass ratio of aqueous ammonia to condensate is 2-4:1.

[0032] Compared with the prior art, the present invention has the following beneficial effects: the synthesis method proposed by the present invention uses an acetone and potassium carbonate system for methylation, and the reaction conditions are mild and non-irritating; the conventional method for synthesizing methyl compounds is avoided, which uses purified water as a solvent, and simultaneously drips liquid alkali and dimethyl sulfate at high temperature to control the pH of the system, which has low controllability, has the risk of material impact, and requires the use of an autoclave.

[0033] This method uses low-temperature sodium borohydride reduction, has a short reaction time, and can directly add hydrochloric acid to form salt after the reaction is completed. The steps are simple, the yield is high, and it is safe. This method uses ammonia water, can remove copper at room temperature, has a suitable filtration speed, and is simple to operate. This method uses isopropanol aqueous solution for salt refining, and the product can be centrifuged, is easy to filter and dry, has good fluidity, and saves time and effort.

[0034] The raw materials used in this synthesis method are cheap and easy to obtain, and the three wastes generated are small, green and environmentally friendly, no heavy metal catalysts are used, and the finished product will not cause drug safety risks due to excessive heavy metals. There is no high temperature and high pressure reaction, the reaction conditions are mild, the required equipment is simple, the operation is convenient, and it has good controllability, which is suitable for large-scale industrial production.

[0035] The purity of the berberine hydrochloride produced by the present invention can reach more than 99.8%, and the single impurity is less than 0.1%, so the safety and effectiveness of the medicine are greatly guaranteed. BRIEF DESCRIPTION OF THE DRAWINGS

[0036] Figure 1 This is a schematic diagram of the test results of batch number CPC-016-M230508;

[0037] Figure 2 This is a schematic table of test results for batch number CPC-016-M230508;

[0038] Figure 3 This is a schematic diagram of the test results of batch number 03623040006;

[0039] Figure 4 This is a table showing the test results for batch number 03623040006;

[0040] Figure 5 This is a schematic diagram of the test results for batch number H241002Z;

[0041] Figure 6 This is a table showing the test results for batch number H241002Z;

[0042] Figure 7 This is a schematic diagram of the test results for batch number H241001Z;

[0043] Figure 8 This is a schematic diagram of the test results for batch number H241001Z;

[0044] Fig. 9 It is a schematic diagram of the process flow of the present invention; DETAILED DESCRIPTION

[0045] The following will be combined with the drawings in the embodiments of the present invention to clearly and completely describe the technical solutions in the embodiments of the present invention. Obviously, the described embodiments are only part of the embodiments of the present invention, not all of the embodiments. Based on the embodiments of the present invention, all other embodiments obtained by ordinary technicians in this field without creative work are within the scope of protection of the present invention.

[0046] Example 1

[0047] like Fig. 9As shown, a method for chemically synthesizing berberine hydrochloride,

[0048] Step 1: Synthesis of methyl compounds:

[0049] Add 100g of o-vanillin and 400g of acetone to a 1L reaction bottle, stir to dissolve, then pour in 115g of anhydrous potassium carbonate, continue to stir evenly, then pour in 98.00g of dimethyl sulfate, heat and stir at 25-35°C for 6h. After the reaction is completed under TLC monitoring, concentrate the acetone to dryness, add 300g of purified water and 400g of toluene to extract, separate the lower aqueous layer, retain the upper organic phase, and concentrate to dryness, i.e. 2,3-dimethoxybenzaldehyde, which can be directly fed to the next step without treatment.

[0050] Step 2: Synthesis of condensation product:

[0051] 105 g of piperidine was directly added to the reaction bottle containing the oily substance in the first step, and the heating and vacuum pump were turned on. The temperature was maintained at 90-100° C. and the pressure was 0.085 MPa, and the reaction was stirred for 1 hour. When the reaction time was up, the temperature was lowered, the nitrogen was depressurized, 400 g of ethanol was added, and the temperature was lowered to below 10° C. after stirring and dissolving. 14 g of sodium borohydride was added to the reaction bottle in batches, 0.5 g each time, and 0.5 g of sodium borohydride was continuously added after stirring for 10 minutes until the addition was completed. The stirring was continued for 1 hour. After the reaction was completed under TLC monitoring, the temperature was kept at 0-10° C., hydrochloric acid was added dropwise to adjust the pH to 2-3, a large amount of solid was precipitated, the temperature was lowered to -5° C. and crystals were grown for 12 hours, centrifuged, and dried at 60° C. for 5 hours to obtain 221 g of an off-white condensation product, and the combined mass yield of the two steps reached 221%; the molar yield was 95.16%.

[0052] Step 3: Synthesis of berberine hydrochloride:

[0053] Add 1105g formic acid and 200g copper sulfate to a 2L reaction bottle, stir and heat to 55-60°C for 30 minutes, continue to add 221g condensate and 155g glyoxal, heat to 90-100°C for reaction, add 30g hydrochloric acid to the reaction system every 1h during the reaction, add 5 times in total, cool to 15-25°C after 5 hours of addition, stir for 30 minutes, centrifuge, wash with purified water until the pH of the centrifuged mother liquor reaches 3-5, stop centrifugation, add the wet cake back to the 3L reaction bottle, add 2210g purified water, stir for 30 minutes, add 552.5g ammonia water, 25- Stir at 35 ° C for 2 hours, cool to 10-20 ° C and filter, wash the filter cake with 221 g of purified water, add the wet filter cake to a 10L reaction bottle, add 6630 g of 5% isopropanol aqueous solution, heat to 85-95 ° C and keep warm for 1 hour, add 22 g of activated carbon and stir for 30 minutes, filter into a 10L reaction bottle pre-filled with 10% hydrochloric acid 1105 g, stir for 30 minutes, cool to 15-25 ° C and stand for 12 hours, centrifuge, wash the filter cake with purified water, and dry at 80 ° C for 10 hours to obtain 157.5 g of berberine hydrochloride product, with a mass yield of 71.27% and a molar yield of 61.72%.

[0054] Example 2

[0055] like Fig. 9 As shown, a method for chemically synthesizing berberine hydrochloride,

[0056] Step 1: Synthesis of methyl compounds:

[0057] To 0.5m 3 200 kg of acetone was pumped into a glass-lined reactor, and 40 kg of o-vanillin was added under stirring. After stirring for 30 minutes to dissolve, 45 kg of anhydrous potassium carbonate was continued to be poured in, and stirred evenly. The reactor cover was covered, and 38.5 kg of dimethyl sulfate was pumped in under vacuum, and the steam was turned on. The temperature was raised to 35-45 ° C and stirred for 10 hours under heat preservation and TLC monitoring (developing agent: n-hexane: petroleum ether = 3:1, ultraviolet 254 nm color development). After the reaction was completed, the vacuum pump was turned on, and the temperature was controlled to 45-55 ° C. The vacuum distillation was carried out to recover the acetone distillation. After the distillation was completed, the cooling water was turned on to cool to 25-35 ° C. 160 kg of purified water and 200 kg of ethyl acetate were pumped in, and the solid was dissolved by stirring. The solid was allowed to stand, separated, and the lower water layer was separated. The upper ethyl acetate layer was retained, and the steam and vacuum pump were turned on. The temperature was raised to 45-55 ° C and the vacuum distillation was carried out to dryness, that is, 2,3-dimethoxybenzaldehyde, which was directly fed to the next step of condensation product preparation;

[0058] Step 2: Synthesis of condensation product:

[0059] Turn on the steam, heat the methyl compound in step 1 to 50-60°C, turn on the vacuum pump, and add 0.5m 342 kg of piperidine was directly added to the glass-lined reactor in vacuum, and the temperature was continued to rise, the temperature in the reactor was maintained at 100-110 ° C, and the pressure was maintained above 0.09 MPa for 2 h. When the reaction time was up, the interlayer circulating water was opened and cooled to 40-50 ° C. 200 kg of anhydrous ethanol was drawn in by vacuum, the temperature was controlled at 40-50 ° C, and the temperature was continued to be cooled to below 10 ° C. The lid of the reactor was opened, and 5.5 kg of sodium borohydride was added to the reactor in batches, 0.5 kg each time, and 0.5 kg was added after stirring for 20 minutes until the addition was completed. Stirring was continued for 2 h, and TLC monitoring was performed (developing agent: petroleum ether: ethyl acetate = 6:1, ultraviolet 254 nm color development). After the reaction was completed, the cold brine was opened, the temperature was lowered below 10 ° C, and hydrochloric acid was added dropwise from the high-level tank to adjust the pH to 2-3, and 32 kg of hydrochloric acid was used. After the addition was completed, a large amount of solid precipitated. The temperature was continued to drop to 0-5°C for crystal growth for 8 hours, centrifuged, rinsed with anhydrous ethanol, and dried at 50-60°C for 5 hours to obtain 86 g of white condensation product. The total mass yield of the two steps reached 215%, and the molar yield was 92.62%.

[0060] Step 3: Synthesis of berberine hydrochloride:

[0061] To 1m 3 Add 439 kg of 90% formic acid to the glass-lined reactor, add 81 kg of anhydrous copper sulfate while stirring, open the interlayer steam, heat to 55-60 ° C and keep warm for 30 minutes, keep the temperature at 55-60 ° C, add 86 kg of condensate first, stir and dissolve, then add 63 kg of 40% glyoxal solution, after the addition, heat the steam to 100-110 ° C for reaction, add 12.9 kg of concentrated hydrochloric acid to the reaction system every 1 hour during the reaction, add 5 times in total, cool to 15-25 ° C after 5 hours of addition, stir for 30 minutes, centrifuge, wash with purified water until the pH of the centrifuged mother liquor reaches 3-5, stop centrifugation, and re-add the wet filter cake to 2m 3 In a glass-lined reactor, add 860 kg of purified water, stir for 30 minutes, then add 258 kg of ammonia water, stir at 35-40 ° C for 2 hours, cool to 10-20 ° C, filter, rinse the filter cake with 86 kg of purified water, and add 5 ml of the wet filter cake. 3 In a glass-lined reactor, add 3440 kg of 5% isopropanol aqueous solution, heat to 85-95 °C and keep warm for 1 hour, add 17.2 kg of activated carbon and stir for 30 minutes, filter to 5 m3 / 3 filled with 430 kg of 10% hydrochloric acid in advance, and 3 In a glass-lined reactor, stir for 30 minutes, turn off the stirring, cool to 15-25°C and let stand for 12 hours, centrifuge, wash the filter cake with purified water, dry with air at 80°C for 10 hours, pass through a 40-mesh sieve, and mix to obtain 64.5 g of berberine hydrochloride product, with a mass yield of 75.88% and a molar yield of 64.94%.

[0062] The total mass yield was 161.25%, and the total molar yield was 60.16%.

[0063] It has been proved that the current commercial products have low purity, with the maximum single impurity reaching more than 0.9%, and multiple impurities do not meet the standard of organic impurities ≤ 0.10% in ICH Q3A. The purity of berberine hydrochloride produced by the present invention can reach more than 99.8%, and the single impurity is less than 0.1%, which greatly guarantees the safety and effectiveness of the drug. The detection results of commercial products and self-made products are shown in the attached Figure 1-8 .

[0064] Although the embodiments of the present invention have been shown and described, as detailed above, it will be understood by those skilled in the art that various changes, modifications, substitutions and variations may be made to the embodiments without departing from the principles and spirit of the present invention, and the scope of the present invention is defined by the appended claims and their equivalents.

Claims

1. A method for chemically synthesizing berberine hydrochloride, characterized in that: The specific steps include: S1: synthesis of methyl compounds; S11: Add o-vanillin and acetone to the reaction bottle, stir to dissolve, then pour in anhydrous potassium carbonate, and continue to stir evenly; S12: Pour dimethyl sulfate into the mixture, heat the mixture to 25-55°C and stir for 6-10 hours. After the reaction is completed under TLC monitoring, concentrate the reaction solution to dryness; S13: adding purified water and organic solvent for extraction, separating the water layer, retaining the organic layer, and concentrating to dryness to obtain a yellow-brown oily substance, namely 2,3-dimethoxybenzaldehyde; S2: Synthesis of condensation products; S21: directly add piperidine to the reaction bottle containing the oil obtained in S13, turn on the heating and vacuum pump, maintain the temperature in the autoclave at 90°C-110°C and the pressure at 0.085 MPa, and stir to react for 1 hour; S22: When the reaction time is up, cool down, release the pressure with nitrogen, add solvent to dilute, stir to dissolve, cool down to below 10°C, add reducing agent to the reaction bottle in batches, and continue stirring for 1-3h after addition; S23: After the reaction was completed by TLC monitoring, the temperature was kept at 0-10°C, hydrochloric acid was added dropwise to adjust the pH value to 2-3, a large amount of solid was precipitated, the temperature was lowered to -5°C, crystallization was carried out for 8-12 hours, centrifuged, and air-dried at 60°C for 5 hours to obtain an off-white condensation product; S3: Synthesis of berberine hydrochloride; S31: Add formic acid and copper sulfate to the reaction bottle, stir and heat to 55-60°C and keep warm for 30 minutes; S32: Continue to add the condensate obtained in S23 and glyoxal, raise the temperature to 90-110°C for reaction, and add concentrated hydrochloric acid 0.1-0.12 m / m to the reaction system every hour during the reaction, for a total of 5 times; S33: After 5 hours of addition, cool to 15-25°C and stir for 30 minutes, centrifuge, wash the filter cake with purified water until the pH of the mother liquor reaches 3-5, and stop centrifugation; S34: Add the wet filter cake back into the reaction flask, add purified water, stir for 30 minutes, then add ammonia water, heat to 25-45°C and stir for 2 hours, cool to 10-20°C and filter, wash the filter cake with purified water, add the wet filter cake into the reaction flask, add 5-10% isopropanol aqueous solution, heat to 85-95°C and keep warm for 1 hour, add activated carbon and stir for 30 minutes; S35: Filter again into a reaction bottle pre-filled with 5-10% hydrochloric acid, stir for 30 minutes, cool to 15-25°C, stand for crystallization for 8-12 hours, centrifuge, wash the filter cake with purified water, and dry at 80°C for 8-10 hours to obtain the berberine hydrochloride product.

2. The method for chemically synthesizing berberine hydrochloride according to claim 1, characterized in that: In S11 and S12, the mass ratio of o-vanillin:potassium carbonate:dimethyl sulfate is 1:1.1-1.2:0.95-0.

98.

3. The method for chemically synthesizing berberine hydrochloride according to claim 1, characterized in that: In S13, the organic solvent is any one of toluene, ethyl acetate and dichloromethane.

4. The method for chemically synthesizing berberine hydrochloride according to claim 1, characterized in that: In the S21, the mass ratio of piperidine to o-vanillin is 1.05-1.08:

1.

5. The method for chemically synthesizing berberine hydrochloride according to claim 1, characterized in that: In S22, the reducing agent is sodium borohydride; the mass ratio of sodium borohydride: o-vanillin is 0.12-0.17:

1. After the reaction is completed, dilution with methanol or ethanol is performed and hydrochloric acid is directly added dropwise to form a salt.

6. The method for chemically synthesizing berberine hydrochloride according to claim 1, characterized in that: In the S31, the concentration of formic acid is any one of 85% formic acid, 88% formic acid, and 90% formic acid, and the content of glyoxal in the S32 is 40%.

7. The method for chemically synthesizing berberine hydrochloride according to claim 6, characterized in that: The mass ratio of condensate: copper sulfate: glyoxal: formic acid in S3 is 1: 0.90-0.95: 0.70-0.75:

5.

8. The method for chemically synthesizing berberine hydrochloride according to claim 1, characterized in that: In the S32, the mass ratio of hydrochloric acid added each time during the reaction: condensate is 0.12-0.17:1, and the interval between each addition is 1 hour.

9. The method for chemically synthesizing berberine hydrochloride according to claim 1, characterized in that: In the S34, the mass ratio of aqueous ammonia to condensate is 2-4:1.

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